The present invention relates to novel indole derivatives useful to down-regulate estrogen receptor expression and to treat neoplasms, especially estrogen-dependent neoplasms such as those associated with breast, ovarian, uterine and cervical tissue, and other disorders associated with estrogen activation.
The present invention provides novel indole derivatives compound of the formula ##STR1## wherein n is an integer from 1 to 12;
P is 0 or 1; PA1 X is from 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, hydroxy, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy and --OC(O)R.sub.6 ; PA1 R.sub.1 is hydrogen, C.sub.1 -C.sub.4 alkyl, or a radical chosen from the group consisting of ##STR2## wherein q is 1, 2, 3, or 4; PA1 Y is each time taken from 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, hydroxy, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, and --OC(O)R.sub.6 ; PA1 G is --NH-- or --(CH.sub.2).sub.r -- wherein r is 1, 2, or 3; PA1 R.sub.7 is C.sub.1 -C.sub.6 alkyl; PA1 R.sub.2 is hydrogen, C.sub.1 -C.sub.4 alkyl, or the radical ##STR3## R.sub.3 is hydrogen or C.sub.1 -C.sub.4 alkyl; R.sub.4 is hydrogen or C.sub.1 -C.sub.4 alkyl; PA1 R.sub.5 is hydrogen, C.sub.1 -C.sub.8 alkyl, or phenyl; or PA1 R.sub.4 and R.sub.5 may be taken together with the adjacent nitrogen to form a ring --CH.sub.2 --CH.sub.2 --G.sub.1 --CH.sub.2 --CH.sub.2 -- wherein G.sub.1 is a direct bond, --NCH.sub.3 --, --CH.sub.2 --, or --O--; and PA1 R.sub.6 is each time taken is independently selected from the group consisting of C.sub.1 -C.sub.4 alkyl, phenyl and substituted phenyl having from 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, hydroxy, C.sub.1 -C.sub.4 alkyl, or C.sub.1 -C.sub.4 alkoxy; PA1 P is 0 or 1; PA1 X is from 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, hydroxy, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy and --OC(O)R.sub.6 ; PA1 R.sub.1 is hydrogen, C.sub.1 -C.sub.4 alkyl, or a radical chosen from the group consisting of ##STR5## wherein q is 1, 2, 3, or 4; PA1 Y is each time taken from 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, hydroxy, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, and --OC(O)R.sub.6 ; PA1 G is --NH-- or --(CH.sub.2).sub.r -- wherein r is 1, 2, or 3; PA1 R.sub.7 is C.sub.1 -C.sub.6 alkyl; PA1 R.sub.2 is hydrogen, C.sub.1 -C.sub.4 alkyl, or the radical ##STR6## R.sub.3 is hydrogen or C.sub.1 -C.sub.4 alkyl; R.sub.4 is hydrogen or C.sub.1 -C.sub.4 alkyl; PA1 R.sub.5 is hydrogen, C.sub.1 -C.sub.8 alkyl, or phenyl; or PA1 R.sub.4 and R.sub.5 may be taken together with the adjacent nitrogen to form a ring --CH.sub.2 --CH.sub.2 --G.sub.1 --CH.sub.2 --CH.sub.2 -- wherein G.sub.1 is a direct bond, --NCH.sub.3 --, --CH.sub.2 --, or --O--; and PA1 R.sub.6 is each time taken is independently selected from the group consisting of C.sub.1 -C.sub.4 alkyl, phenyl and substituted phenyl having from 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, hydroxy, C.sub.1 -C.sub.4 alkyl, or C.sub.1 -C.sub.4 alkoxy; PA1 a) the term "C.sub.1 -C.sub.4 alkyl" refers to a saturated straight or branched chain hydrocarbyl radical of from one to four carbon atoms and includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, and tertiary butyl; PA1 b) the term "C.sub.1 -C.sub.8 alkyl" refers to saturated straight or branched chain hydrocarbyl radicals of one to eight, including methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tertiary butyl, pentyl, isopentyl, hexyl, 2,3-dimethyl-2-butyl, heptyl, 2,2-dimethyl-3-pentyl, 2-methyl-2-hexyl, octyl, 4-methyl-3-heptyl and the like; PA1 c) the term "halogen", "halo", "halide", or "Hal" refers to fluorine atom, chlorine atom, bromine atom, or iodine atom; PA1 d) the term "C.sub.1 -C.sub.4 alkoxy" refers to a straight or branched alkoxy group containing from one to four carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, and the like; PA1 e) the designation "--C(O)--" refers to a carbonyl group of the formula: ##STR7## f) the term "phenyl" refers to ##STR8## g) the term "substituted phenyl" refers to ##STR9## wherein Y is from 1 to 3 substituents independently chosen from the group consisting of hydrogen, halogen, hydroxy, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, and --OC(O)R.sub.6 wherein R.sub.6 is C.sub.1 -C.sub.4 alkyl, phenyl or substituted phenyl having from 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, hydroxy, C.sub.1 -C.sub.4 alkyl, or C.sub.1 -C.sub.4 alkoxy; PA1 h) the term "benzyl" refers to ##STR10## i) the term "substituted benzyl" refers to ##STR11## wherein Y is from 1 to 3 substituents independently chosen from the group consisting of hydrogen, halogen, hydroxy, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, and --OC(O)R.sub.6 wherein R.sub.6 is C.sub.1 -C.sub.4 alkyl, phenyl or substituted phenyl having from 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, hydroxy, C.sub.1 -C.sub.4 alkyl, or C.sub.1 -C.sub.4 alkoxy; PA1 j) the term "benzoyl" refers to ##STR12## k) the term "substituted benzoyl" refers to ##STR13## wherein Y is from 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, hydroxy, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, and --OC(O)R.sub.6 wherein R.sub.6 is C.sub.1 -C.sub.4 alkyl, phenyl or substituted phenyl having from 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, hydroxy, C.sub.1 -C.sub.4 alkyl, or C.sub.1 -C.sub.4 alkoxy; PA1 l) the term "Pg" refers to a protecting group as described in Protecting Groups in Organic Synthesis by T. Greene as is well known and appreciated by those skilled in the art; and PA1 m) the term "pharmaceutically acceptable salts" refers to base addition salts including any non-toxic organic or inorganic basic addition salts of a compound of the formula provided or any of its intermediates. Illustrative bases which form suitable salts include alkali metal or alkaline-earth metal hydroxides such as sodium, potassium, calcium, magnesium, or barium hydroxides; ammonia, and aliphatic, cyclic, or aromatic organic amines such as methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, isopropyldiethylamine, pyridine and picoline. PA1 n) the term "C.sub.1 -C.sub.6 alkyl" refers to a saturated straight or branched chain hydrocarbyl radical of from one to six carbon atoms and includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tertiary butyl, pentyl, hexyl, cyclopentyl, cyclohexyl and the like; PA1 o) the designation ##STR14## when G is --NH-- refers to wherein Y is from 1 to 3 substituents independently chosen from the group consisting of hydrogen, halogen, hydroxy, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, and --OC(O)R.sub.6 wherein R.sub.6 is C.sub.1 -C.sub.4 ##STR15## alkyl, phenyl or substituted phenyl having from 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, hydroxy, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, and --OC(O)R.sub.6 wherein R.sub.6 is C.sub.1 -C.sub.4 alkyl, phenyl or substituted phenyl having from 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, hydroxy, C.sub.1 -C.sub.4 alkyl, or C.sub.1 -C.sub.4 alkoxy; and PA1 when G is --(CH.sub.2).sub.r -- refers to ##STR16## wherein r is 1, 2, or 3; and PA1 Y is from 1 to 3 substituents independently chosen from the group consisting of hydrogen, halogen, hydroxy, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, and --OC(O)R.sub.6 wherein R.sub.6 is C.sub.1 -C.sub.4 alkyl, phenyl or substituted phenyl having from 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, hydroxy, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, and --OC(O)R.sub.6 wherein R.sub.6 is C.sub.1 -C.sub.4 alkyl, phenyl or substituted phenyl having from 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, hydroxy, C.sub.1 -C.sub.4 alkyl, or C.sub.1 -C.sub.4 alkoxy.
with the proviso that when n is 1 then at least one R.sub.1, R.sub.2, R.sub.3, R.sub.4, and R.sub.5 is not hydrogen;
or their pharmaceutically acceptable salts.
The present invention includes methods to treat neoplasms or of controlling the growth of a neoplasm in a patient afflicted with a neoplastic disease comprising administration of a compound of formula provided.
Another embodiment of the present invention is a method of prophylactically treating a patient at risk of developing a neoplastic disease state comprising administration of a compound of the formula provided.
Breast cancer is the leading cause of cancer among women and the second biggest killer of women. The age-adjusted incidence rate for breast cancer among women in the United States between 1986 and 1987 was 108.9 per 100,000. This is over two times greater than the age-adjusted incidence rate for cancer of the colon, the second leading form of cancer in women. Satariano, W. A., Aging, Comorbidity, and Breast Cancer Survival: An Epidemiologic View. in The Underlying Molecular, Cellular, and Immunological Factors in Cancer and Aging, (Young, S. S. and Warner, H. R., eds.) Plenum Press, New York, pp. 1-11, 1993.
In women, the risk of developing breast cancer increases dramatically with age (Pike et al., "The epidemiology of breast cancer as it relates to menarche pregnancy and menopause." in Banbury Report 8: Hormones and Breast Cancer (Pike, M. C., Siiteri, P. K. and Welsch, C. W., eds.), Cold Spring Harbor Laboratory, pp. 3-21, 1981). The risk of a woman developing breast cancer by age 30 is about one in 2,500. The risk of a woman developing breast cancer by age 60 is one in 24. Although significant advances have been made regarding the treatment options for those with breast cancer, the mortality rate for breast cancer remains high.
The difference of incidence of breast cancer among pre- and post-menopausal women suggests exposure to estrogen is critical to onset and malignant progression of breast cancer. This conclusion is strengthened by comparing the incidence of breast cancer in women and men; women develop breast cancer about 100 times the frequency of men. Ovariectomy and/or antiestrogenic and antiprogestational drugs have been successfully used in treatment of breast cancer (Iino, Y. et al., Antiestrogen therapy for breast cancer: Current strategies and potential causes for therapeutic failure, in: Regulatory Mechanisms in Breast Cancer, Lippman, M. E. and Dickson, R. B., eds., Klower Academic Publishers, Norwell, Mass., pp. 221-238, 1990).
The steroid dependence of some breast cancers has been known for almost 100 years and both endocrine therapy and surgery (ovariectomy/adrenalectromy) have been used for the control of this disease. Steroid dependence has been explained by varying estrogen receptor levels in breast tumors. Of those tumors possessing detectable estrogen receptor, determined by cytosols containing greater than ten fmol of estrogen receptor per mg of protein, over 60% have proved to be responsive to endocrine therapy, whereas those containing less than ten fmol of receptor per mg of protein, less than 5% have responded.
Estrogens are thought to regulate the growth of tumor cells via estrogen receptors (ERs) present in the cytosol. ERs are "activated" upon binding with ligands such as estradiol and estrogen. Once bound, the estrogen-estrogen receptor complex migrates through the cytosol and into the nucleus, where the complex is thought to initiate the transcription of other proteins. The binding of estrogen to the estrogen receptor exposes groups which enable the complex to form tight complexes with both acidic and basic macromolecules such as DNA, acidic polysaccharides, histones and other basic proteins. After binding, a series of events follows, including dissociation from heat shock proteins, dimerization and binding to DNA at an estrogen response element (ERE). After binding to the DNA, the activated estrogen-ER complex is thought to interact with transcription factors and stabilize preinitiation complex at the promoter, allowing RNA polymerase to initiate gene transcription and resulting in transcription of mRNA. Subsequent steps in the transformation of normal cells to tumor cells has yet to be elucidated; but prevention of estrogen activation of breast cells is thought to prevent subsequent development of uncontrolled cellular growth resulting from estrogen-activated transcription.
Many of the receptors for virtually all relevant steroid hormones have been cloned and sequenced. As a result, it has been discovered that the steroid hormone receptors belong to a large superfamily of nuclear receptors, that includes the receptors for retinoic acid, thyroid hormones and several genes for which a physiological ligand is as of yet not know, designated "orphan" receptors.
Common to all members of the nuclear receptor family is a short DNA-binding domain composed of about 70 amino acid residues containing many conserved cysteines. Eight of these conserved cysteines can be organized into two so-called "zinc" fingers, a structure first proposed for the transcription factor FTIIIA from Xenopus laevis. Each zinc finger contains four cysteine residues tetrahedrally coordinating a zinc ion.
Based on sequence conservation of the two zinc "fingers", each of which is encoded by a separate exon, the nuclear receptor genes have been classified into two subfamilies. The glucocorticoid receptor (GR) is the prototype of the smaller subfamily that includes the progesterone receptor (PR), androgen receptor and the mineralocorticoid receptor. The prototype of the larger subfamily is the estrogen receptor (ER) and this group includes the vitamin D.sub.3 receptor, the various thyroid hormone receptors, the receptors for retinoic acid and many of the orphan receptors.
ER has been characterized as having two activation domains, referred to as TAF1 (located at the amino terminus of the receptor) and TAF2 (located in the 60 amino acidcarboxyl terminus). TAF1 activation is estrogen independent; once delivered to DNA it can activate transcription. Studies on human ER mutants have demonstrated that the action of TAF1 and TAF2 depends on the promoter context; on certain promoters, both the TAF1 and TAF2 activations are required for transcriptional activity. On other promoters, the TAF1 and TAF2 activators function independently.
Significant research has been conducted on estrogen agonists and antagonists useful to treat neoplasms associated with the breast. The antiestrogen tamoxifen is widely used in the endocrine therapy of hormone-dependent breast cancer. About 40% of the patients do not respond to tamoxifen treatment despite the presence of ERs in the malignant tissue. Maass, H., et al., Cancer, 46:2783 (1980). One possible reason for failure may be due to the weak estrogenic activity of tamoxifen or due to the incomplete antagonism of tamoxifen. The antagonist activity of tamoxifen is thought to arise from its intrinsic inability to activate the TAF2 function of the estrogen receptor. Tzukerman, M. T., et al., Mol. Endocrin., 8(1):21-30 (1994). However, toxicological problems associated with tamoxifen treatment, including tumor flares, vaginal cornification and hypercalciemia, make long term tamoxifen treatment undesirable in some situations. In addition, some tumors are tamoxifen-resistant despite the existence of estrogen receptors. Therefore, there is a need for a better method of treating estrogen-dependent neoplasms.
In an effort to develop "pure" antiestrogen drugs, researchers investigated estrogen-like compounds. One of the earliest was ICI 164,384 (11-(3-17.beta.-dihydroxyoestra-1,3,-5(10)-trien-7.alpha.-yl)-N-n-butyl-N- methylundecanamide). ICI 164,384 has been shown to inhibit DNA binding of the mouse estrogen receptor by interfering with receptor dimerization. Fawell, S. E., et al., Proc. Nat'l. Acad. Sci. USA, 87:6883-6887 (1990). Von Angerer and his colleagues have developed derivatives of 2-phenylindole with an aminoalkyl chain at the indole nitrogen. Von Angerer, E., et al., J. Med. Chem. 1990, 33, 2635-2640. These 1-(amino-alkyl)-2-phenylindoles are estrogen antagonists and were thought to avoid the problems associated with the estrogenic activity of tamoxifen.
The statistics of incidence of breast cancer in men and women, pre and postmenopausal, indicates that exposure of the mammary gland to ovarian estrogens and progestins is critical to onset and malignant progression of breast cancer. Other growth regulatory mechanisms may also play a role in the loss of ovarian function during menopause and may also play a role in the onset of breast cancer. Furthermore, a genetic factor(s), inherited familial autosomal dominant genes, are also thought to influence the risk of breast cancer.
ERs are widely distributed throughout the body in organ tissues associated with female reproduction, e.g., vagina, cervix, corpus uteri, fallopian tubes, ovaries and breast. The presence of ERs are not limited to cells in female reproductive organs; ERs are also found in cells throughout the body, including the uterus (Quarmby, V. E., et al., Endocrin., 114:694-702 (1984)!, bone Yamamoto, T. T., et al, Proc. Natl. Acad. Sci. USA, 48:2172-2176 (1990); Migliaccio, S. et al., Endocrin., 130:1756-1758 (1992); Eriksen E. F., et al, Science, 241:84-86 (1988)!, kidney Davidoff, M., et al., Histochem., 9:39-48 (1980)!, and brain Fox, T. O., Nature, 258:441-443 (1975)!. As of yet, the understanding of the role these ERs play in normal and disease states is not well defined. Given the pleotrophic effect estrogen is known to have on cells, it is logical to expect that gene transcription resulting from activation of ERs contributes uncontrolled cell growth (neoplasia) and/or cellular dysfunction in ER-expressing cells.
Heightened estrogen activity may play a role in the symptoms associated with a number of seemingly unrelated diseases. Autoimmune diseases appear to be due to the failure of normal mechanisms of self-tolerance. Some autoimmune diseases involve an immune response against self-molecules that are expressed in anatomically remote sites; others are due to immune responses to ubiquitous nuclear and cytomplasmic antigens. Human autoimmune diseases have been classified in several ways; many have been linked to genes encoding the major histocompatibilty complex (MHC), class I or class II. Susceptibility to autoimmune diseases is also associated with environmental factors, such as preceding infection, and endocrine factors. Many autoimmune diseases have a peak incidence at or shortly after puberty and a second peak incidence in the forties and fifties, ages when the endocrine system is changing. Autoimmune diseases are generally worse in women than in men, often flaring after pregnancy, and approximately two thirds of those afflicted with autoimmune diseases are women. Therefore, estrogen activity is implicated in the etiology of autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, insulin-dependent diabetes, Graves' disease, myasthenia gravis, and systemic lupus erythematosus. Multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus and myasthenia gravis typically proceed with periods of deterioration and remission. The periods of deterioration correlate with female hormones, stress and infection. An explanation for these observations may be that estrogen activation of the estrogen receptor results in gene transcription of the nearby gene encoding gamma-interferon, which aggravates the autoimmune process. Therefore, prevention of estrogen-induced transcription would be expected to alleviate or even prevent the symptoms of such diseases.